Preparation of β-lactam compounds, and intermediates therefor

ABSTRACT

A process for preparing a β-lactam compound of the formula (I): ##STR1## which comprises cyclization of an azetidinone derivative of the formula: ##STR2## is provided in which R 1  is hydrogen, alkyl which is optionally substituted, or amino which is optionally substituted; R 2  is a carboxy-protecting group; and X is alkylene which is optionally intervened by --O-- or --S--, and/or which is optionally substituted; and R 3  is aryl which is optionally substituted.

This application is a division of now abandoned application Ser. No.08/190,608, filed Feb. 2, 1994.

FIELD OF THE INVENTION

The present invention relates to a useful process for preparing β-lactamantibiotics, and specifically to a process for preparing carbapenamderivatives, which are useful intermediates for preparation of β-lactamantibiotics, as well as intermediates which are useful for the process.More specifically, the present invention relates to a process forpreparation of β-lactam antibiotics which comprises cyclization of noveland useful azetidinone derivatives, as well as such azetidinonederivatives.

PRIOR ART

Currently, β-lactam antibiotics are clinically used in treatment ofinfections. The β-lactam antibiotics may be classified, and includeantibiotics having carbapenam or carbapenem nucleus, which belong tonewer types of antibiotics.

A process for preparation of carbapenam or carbapenem antibiotics mayinvolve a process which comprises making derivatives having carbapenamnucleus from azetidinone derivatives. Such process is described in EP0037080 A1, and is as shown below: ##STR3## This process involvescyclization which comprises heating the diazo compound at 50°-100 ° C.,and preferably heating in the presence of catalyst, CuSO₄, Pd(OAc)₂, orRh₂ (OAc)₄. To date, the process has been utilized industrially at largescale.

However, the above process is disadvantageous in that the azide reagentand the diazo compound used in the process are explosive while they areheating. In other words, it is very dangerous to treat a large amount ofthe diazo compound. Accordingly, the above process is not desired asindustrial process for preparation of carbapenem antibiotics.

Thus, the applicants have studied and found a safe and convenientprocess for preparation of carbapenem antibiotics, which does notcomprise using the above azide reagent and diazo compound.

DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing a β-lactamcompound of the formula (I): ##STR4## in which R¹ is hydrogen, alkylwhich is optionally substituted, or amino which is optionallysubstituted;

R² is a carboxy-protecting group; and

X is alkylene which is optionally intervened by --O-- or --S--, and/orwhich is optionally substituted.

which comprises cyclization of an azetidinone derivative of the formula:##STR5## wherein R¹, R², and X are as defined above, and R³ is arylwhich is optionally substituted.

In the above formula, the term "alkyl" in the definition of R¹ refers toa straight or branched C₁ -C₆ alkyl group, and preferably refers to astraight or branched C₁ -C₄ alkyl group. Substituents on the alkyl areexemplified by halogen, hydroxy which may be substituted by ahydroxy-protecting group, and so on. The protecting groups of hydroxyinclude, for example, (lower alkoxy)carbonyl such as C₁ -C₄alkoxycarbony (for example, t-butyloxycarbonyl), halogenated (loweralkoxy) carbonyl such as halogenated (C₁ -C₃) alkoxycarbonyl (forexample, 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbony), aryl(lower alkoxy) carbonyl such as phenyl (C₁ -C₄) alkoxycarbony of whichbenzene ring may have substituent(s) (for example, benzyloxycarbonyl,o-nitrobenzyloxycarbony, p-nitrobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl), tri-(lower alkyl)silyl such as tri-(C₁-C₄)alkylsilyl (for example, trimethylsilyl, t-butyldimethylsilyl),substituted methyl such as C₁ -C₄ alkoxymethyl (for example,methoxymethyl), C₁ -C₄ alkoxy (C₁ -C₄)alkoxymethyl (for example,2-methoxyethoxymethyl), C₁ -C₄ alkylthiomethyl (for example,methylthiomethyl), tetrahydropyranyl, and the like conventional groups.Preferably, R¹ is hydroxyethyl.

Substituent on amino group of R¹ is preferably amino-protecting grouphaving 1 to 20 carbon atoms which can be removed without anyinconvenient changes in any other moiety on the molecule, and which havebeen used in the field of penicillin and cephalosporin. Typicalsubstituents include an alkyl having 1 to 8 carbon atoms (t-butyl,methoxymethyl, methoxyethoxymethyl, trichloroethyl, tetrahydropyranyl,and so on), an aralkyl having 7 to 20 carbon atoms (benzyl,diphenylmethyl, trityl, methoxybenzyl, nitrobenzyl, methylbenzyl, and soon), an arylthio having 6 to 12 carbon atoms (nitrophenylthio, and soon), an alkylidene having 1 to 8 carbon atoms, an aralkylidene having 7to 14 carbon atoms (benzylidene, or substituted benzylidene), an acyl[alkanoyl having 1 to 8 carbon atoms (formyl, acetyl, chloroacetyl,trichloroacetyl, trifluoroacetyl, and so on), an aralkanoyl having 7 to15 carbon atoms (phenylacetyl, phenylglycyl, phenylglycosyl,phenylmaronyl, thiazolylacetyl, aminothiazolyl-α-hydroxyiminoacetyl, andso on), an aroyl having 7 to 15 carbon atoms (benzoyl, nitrobenzoyl, andso on), an alkoxycarbonyl having 2 to 12 carbon atoms (in which thealkyl moiety is methyl, ethyl, propyl, cyclopropylethyl, isopropyl,butyl, pentyl, hexyl, isobutyl, trichloroethyl, pyridylmethyl,cyclopentyl, cyclohexyl, and so on), an aralkoxycarbonyl having 8 to 15carbon atoms (in which the aralkyl moiety is benzyl, diphenylmethyl,nitrobenzyl, and so on), a dibasic acid acyl having 3 to 10 carbon atoms(succinyl, phthaloyl, and so on), a halosulfonyl, a phosphate acylhaving 0 to 10 carbon atoms (dialkoxyphophoryl, dichlorophophoryl), andso on], a trialkylsilyl having 3 to 15 carbon atoms, a trialkylstannylhaving 3 to 15 carbon atoms, and so on, each of which groups may befurther substituted.

In the above formula, the term "carboxy-protecting group" in R² refers,for example, to lower alkyl such as C₁ -C₄ alkyl (for example, methyl,ethyl, isopropyl, t-butyl), halogenated lower alkyl such as C₁ -C₃ alkyl(for example, 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxymethylsuch as C₁ -C₄ alkoxymethyl (methoxymethyl, ethoxylmethyl,isobutoxymethyl), lower aliphatic acyloxymethyl such as C₁ -C₅alkanoyloxymethyl (for example, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl), lower alkoxycarbonyloxyethyl suchas 1-(C₁ -C₄ alkoxycarbonyloxy)ethyl (for example,1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), a lower alkenylwhich may be substituted, such as C₃ -C₁₀ alkenyl which may besubstituted by C₁ -C₄ alkyl or phenyl (for example, allyl,2-methylallyl, 3-methylallyl, 3-phenylallyl), monoaryl(lower)alkyl whichmay be substituted, such as phenyl (C₁ -C₄) alkyl of which benzene ringmay be substituted by C₁ -C₄ alkoxy, nitro, halogen, and so on (forexample, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-chlorobenzyl), diaryl(lower)alkyl which may besubstituted, such as diphenyl(C₁ -C₄) alkyl which may be substituted byC₁ -C₄ alkoxy and so on (for example, diphenylmethyl,di-p-anisylmethyl), an aryl such as phenyl which may be substituted byhalogen, nitro, C₁ -C₄ alkoxy, and so on (for example, phenyl,p-chlorophenyl, 2,4,5-trichlorophenyl, p-nitrophenyl, o-nitrophenyl,p-methoxyphenyl), a heteroaryl such as pyridyl or pyrimidyl which may besubstituted by C₁ -C₄ alkyl (for example, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 2-(4, 6-dimethyl)pyrimidyl), phthalydyl, and thelike conventional groups which will protect the carboxy group.

In the above formula, "an aryl" in R³ includes phenyl, naphthyl, whichmay be substituted by halogen, lower alkyl, lower alkoxy, hydroxy,amino, nitro, and so on. Particularly preferred group is phenyl.

An "alkylene" in the definition of X includes preferably C₁ -C₅alkylene, more preferably X includes C₁ -C₃ alkylene, and exemplified bymethylene, ethylene, propylene, butylene, and pentylene. This alkylenecan be intervened by --O--, or --S--, and/or be substituted by asubstitituent (e.q. lower alkyl, lower alkoxy, lower alkylthio, aryl,lower alkenyl, etc.). This includes --OCH₂ --, --SCH₂ --, --O(CH₂)₂ --,--S(CH₂)₂ --, or a group of the formula: ##STR6## One of the preferredgroups is an "alkylidene group" of the formula:

    C.sub.n H.sub.2n+1 CH═

wherein n is an integer which is equal to or above 0, and preferably, aninteger of 0 to 5. The alkylidene includes ethylidene (CH₃ CH═),propylidene (CH₃ CH₂ CH═), isopropylidene ((CH₃)₂ C═), and so on.Preferably, the alkylidene is ethylidene.

The process of the present invention involves the step which comprisessynthesizing β-lactam compounds from azetidinone derivatives. Thereaction of the process is conducted in a solvent which does not affordan adverse effect to the reaction, and preferably in an aprotic solvent.The preferred aprotic solvent includes methylene chloride, benzene,toluene, tetrahydrofuran, and so on.

The reaction is substantially completed within several ten minutes toseveral ten hours at -20° C. to 100° C., preferably at -10° C. to 50°C., and most preferably under ice-cooling to at room temperature.

The present process is preferably conducted in the presence of acatalyst. The catalyst may effect cyclization of the compound (II).Preferably, the catalyst includes transition metals, and in particularrhodium salts. The rhodium salts include a salt forming with acarboxylic acid, and specifically include acetate (Rh₂ (OAc)₄),trifluoroacetate (Rh₂ (CF₃ CO₂)₄), pivalate (Rh₂ ((CH₃)₃ CCO₂)₄), andoctanate (Rh₂ (C₇ H₁₅ COO)₄). The amount of the catalyst variesdepending on kinds of the used catalyst, reaction temperature, and soon, and preferably, the amount is 0.001 to 0.1 mole per mole ofazetidinone derivative.

According to other embodiment, the present invention provides a novelazetidinone derivative of the formula (II): ##STR7## wherein R¹, R², R³,and X are as defined above. The azetidinone derivative is produced byreacting a compound of the formula (III): ##STR8## wherein R¹, R², and Xare as defined above, with a compound of the formula:

    R.sup.3 --I(Q).sub.2

wherein R³ is as defined above, and Q is a substituent derived from ananion part of an acid.

In the formula: R³ --I(Q)₂, Q is a substituent derived from an anionpart of an acid including an organic acid, and an inorganic acid. Theorganic acid includes carboxylic acids and sulfonic acids. The inorganicacid includes halogenated hydro-acids such as HF, HCl, HBr. A preferredcompound of R³ --I(Q)₂ includes PhI(OCOCH₃)₂, PhI(OCOCF₃)₂, PhIF₂. Thereaction of the process is conducted in a solvent in the presence of abase. The solvents include ones which do not afford an adverse effect tothe reaction, and preferably the solvent is an alcoholic solvent such asmethanol. An organic base (tertiary amine, aromatic base), or aninorganic base (oxides of alkali metals or alkaline earth metals,hydroxides, carbonates, bicarbonates, and so on) can be used as thebase.

The compound of the formula (III) can be produced according to the knownmethod in the field of β-lactam antibiotics.

The compound of the formula (II) also can be produced using (PhIO)n,PhI(OH)OTs, etc. instead of R³ --I(Q)₂ according to the method of theliterature [Varvoglis A., Synthesis, 709 (1984), and Moriarty R. H.,Valid R. K., Synthesis, 431 (1990)].

The present invention provides a process for preparing a β-lactamcompound of the formula (I) via the azetidinone derivative of theformula (II), and specifically a process for preparing a β-lactamcompound of the formula (I): ##STR9## in which R¹, R², and X are asdefined above; which comprises reacting a compound of the formula (III):##STR10## wherein R¹, R², and X are as defined above, with a compound ofthe formula:

    R.sup.3 --I(Q).sub.2

wherein R³ is as defined above to give the azetidinone derivative of theformula: ##STR11## wherein R¹, R², R³, and X are as defined above andthen, the latter derivative is cyclized.

The compound of the formula (I) obtained from the process of the presentinvention can be used as starting material for the compound of theformula: ##STR12## which is described, for example, in the JapanesePatent Application No. 221767/1992. For example, the compound (I) isesterified by reacting with phosphate to give an activated compound,which is reacted with a thiol compound to give 2-thio-carbapenemcompound; or chlorinated to give a 3-chloro-carbacephem compound.

EXAMPLES

The present invention is illustrated in more detail by the followingExamples and Reference Example, but should not be construed to belimited to the scope of the Examples.

Example 1 Diphenylmethyl (1R, 5R,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate(Compound 3) ##STR13## I.(3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(R)-3-diphenylmethoxycarbonyl-1-methyl-2-oxo-3-phenyliodoniopropyl]-azetidin-2-one(Compound 2)

(Method A) Iodobenzene diacetate (1.68 g, 5.22 mmole) was dissolved in20 ml of methanol, and 1.26N solution of sodium methylate (8.28 ml, 10.4mmole) was added thereto, and the mixture was stirred at roomtemperature for 10 minutes. Then, compound 1:(3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(R)-3-diphenylmethoxycarbonyl-1-methyl-2-oxopropyl]-azetidin-2-one(2.00 g, 5.06 mmole) was added thereto, and the resultant mixture wasstirred at room temperature for 20 minutes. The reaction mixture wasconcentrated, and ethyl acetate (30 ml) was added to the residue, andthen the precipitated sodium acetate was filtered off. The filtrate wasconcentrated, and ethyl acetate (10 ml) and hexane (40 ml) were added tothe residue. The resultant crystals were filtered to yield compound 2(2.70 g, 89%) as a pale yellow crystal.

(Method B) Iodobenzene diacetate (420 mg, 1.30 mmole) was dissolved in 5ml of methanol, and potassium carbonate (180 mg, 1.30 mmole) was addedthereto, and the mixture was stirred at room temperature for 10 minutes.Then, compound 1 (500 mg, 1.27 mmole) was added thereto, and theresultant mixture was stirred at room temperature for 20 minutes. Thereaction mixture was concentrated, and ethyl acetate (8 ml) was added tothe residue, and then the precipitated potassium acetate was filteredoff. The filtrate was concentrated, and ethyl acetate (4 ml) and hexane(20 ml) were added to the residue. The resultant crystals were filteredto yield compound 2 (702 mg, 93%) as a pale yellow crystal.

Compound 2: mp; 109°-111° C., ¹ H-NMR(CDCl₃) δ:7.66 (2H, d, J=8.2 Hz),7.53 (1H, t, J=8.2 Hz), 7.4-7.2 (12H,m), 6.86 (1H,s), 6.05 (1H, brs),4.14-3.88 (2H, m), 3.77 (1H, dd, J=1.8 Hz, 8.3 Hz), 2.69 (1H, dd, J=1.8Hz, 8.8 Hz), 1.26 (3H, d, J=6.4 Hz), 1.20 (3H, d, J=6.8 Hz); IR (CHCl₃)cm⁻¹ : 3400 (br), 1752, 1655, 1560, 1545, 1538, 1380, 1370, 1340.

II. The Title Compound 3

To the suspension which had been prepared by suspending compound 2obtained in the step I (200 mg, 0.335 mmole) in 6 ml of dichloromethane,was added rhodium acetate (1.5 mg, 0.0034 mmole), and the mixture wasstirred at room temperature for 20 minutes. The reaction mixture wasdiluted with dichloromethane, and the dilution was washed once withwater, once with brine, dried over anhydrous sodium sulfate, andconcentrated. The resultant residue was purified by chromatography(using toluene:ethyl acetate:acetic acid=250:250:1 as an eluent) toyield 113 mg of compound 3 as a colorless foam (86%).

Compound 3: ¹ H-NMR (CDCl₃) δ:7.4-7.2 (10H, m), 6.87 (1H, s), 4.76 (1H,s), 4.29 (1H, quintet, J=6.5 Hz), 4.22 (1H, dd, J=2.3 Hz, 7.9 Hz), 3.24(1H, dd, J=2.3 Hz, 7.0 Hz), 2.77 (1H, quintet, J=7.7 Hz), 1.37 (3H, d,J=6.2 Hz), 1.20 (3H, d, J=7.8 Hz); IR (CHCl₃) cm⁻¹ : 3600, 3500 (br),1765, 1750 (shoulder), 1495, 1455, 1380, 1360, 1295.

Example 2 p-Nitrobenzyl (1R, 5R,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carba-2-penem-3-carboxylate(Compound 6) ##STR14## I. (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo-3-phenyliodoniopropyl]-azetidin-2-one(Compound 5)

Compound 4, (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-3-p-nitorobenzyloxycarbonyl-2-oxopropyl]-azetidin-2-one(500 mg, 1.04 mmole) was dissolved in 1 ml of methanol, and the solutionwas cooled up to -5 ° C. To the cooled solution were added a solution ofpotassium hydroxide (136 mg, 2.08 mmole) in 1 ml of methanol, and then,a solution of iodobenzene diacetate (337 mg, 1.05 mmole) in 2 ml ofmethanol, and the resultant mixture was stirred at -10° to -5 ° C. for40 minutes. To the mixture was added ice-cold water, and the resultantmixture was extracted twice with dichloromethane. The organic phase wasdried over anhydrous sodium sulfate, and then concentrated to yield 606mg of compound 5 as pale yellow crystals (86%).

Compound 5: ¹ H-NMR (CDCl₃)δ: 8.18-8.14 (2H, m), 7.7-7.3 (7H, m), 6.10(1H, brs), 5.17 (2H, s), 4.36-4.22 (1H, m), 4.22-4.08 (1H, m), 3.86 (1H,dd, J=2.1 Hz, 4.1 Hz), 3.04-2.97 (1H, m), 1.17 (3H, d, J=6.8 Hz), 1.14(3H, d, J=6.2 Hz), 0.84 (9H, s), 0.05 (3H, s), 0.04 (3H, s).

II. The Title Compound 6

To the solution which had been prepared by dissolving compound 5obtained above (120 mg, 0.176 mmole) in 1 ml of dichloromethane, wasadded 8 mg of rhodium acetate (0.018 mmole), and the mixture was stirredfor 20 minutes. The reaction mixture was filtered, and the filtrate wasconcentrated. The residue which contained p-nitrobenzyl (1R, 5R,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-methyl-2-oxo-1-carba-2-penem-3-carboxylatewas dissolved in 2 ml of acetonitrile, and 44 μl of diphenylchlorophosphate (0.212 mmole) and 37 μl of diisopropylethylamine (0.212mmole) were added thereto under ice-cooling, and the resultant mixturewas stirred for 50 minutes. The reaction mixture was diluted with ethylacetate, and washed each once with diluted hydrochloric acid, 5% aqueoussodium bicarbonate, and brine. Then, the organic phase was dried overanhydrous sodium sulfate, and concentrated. The residue was purified bychromatography (using toluene: ethyl acetate=10:1 as an eluent) to yield50 mg of compound 6 as colorless foam (40%).

Compound 6: ¹ H-NMR (CDCl₃)δ:8.2-8.1 (2H, m), 7.6-7.15 (12H, m), 5.33,5.23 (2H, ABq, J=13.6 Hz), 4.32-4.15 (1H, m), 4.19 (1H, dd, J=3.0 Hz,7.6 Hz), 3.54-3.34 (1H, m), 3.28 (1H, dd, J=3.0 Hz, 5.7 Hz), 1.23 (3H,d, J=6 Hz), 1.20 (3H, d, J=6 Hz), 0.86 (9H, s), 0.07 (3H, s), 0.06 (3H,s).

Example 3 p-Nitrobenzyl (1R, 5R,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate(Compound 13) ##STR15## I. (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(R)-1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo-3-phenyliodonyopropyl]-azetidin-2-one(Compound 12)

To the solution which had been prepared by dissolving 456 mg ofiodobenzene diacetate in 5 ml of methanol, was added 196 mg of potassiumcarbonate (1.42 mmole), and the mixture was stirred at room temperaturefor 20 minutes. The resultant mixture was cooled up to -78 ° C., and 500mg of compound 11, (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[(R)-1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxopropyl]-azetidin-2-onewas added thereto, and the mixture was stirred at the same temperaturefor 30 minutes. The reaction mixture was concentrated, and 8 ml of ethylacetate was added to the residue. The insoluble potassium acetate wasfiltered off, and the filtrate was concentrated. To the residue wereadded 5 ml of ethyl acetate and 15 ml of hexane to form crystals, whichwere obtained by filtration. The resultant crystals were washed withwater, and dried to yield 676 mg of compound 12 as white crystals (87%).

Compound 12: mp: 88°-89° C., ¹ H-NMR (CDCl₃)δ:8.17 (2H, d, J=8.5 Hz),7.74 (2H, d, J=8.5 Hz), 7.58 (1H, t, J=8 Hz), 7.43-7.35 (4H, m), 6.15(1H, brs), 5.20 (2H, s), 4.2-3.85 (2H, m), 3.81 (1H, dd, J=1.9 Hz, 8.5Hz), 3.74 (1H, s), 2.72 (1H, brd, J=8 Hz), 1.28 (3H, d, J=6.8 Hz), 1.24(3H, d, J=7.4 Hz). IR (CHCl₃)cm⁻¹ : 3400 (br), 1750, 1655, 1520, 1380,1370, 1340.

II The Title Compound 13

To the solution which had been prepared by dissolving 200 mg of compound12 obtained above (0.353 mmole) in 6 ml of dichloromethane, was added1.6 mg of rhodium acetate (0.0036 mmole), and the mixture was stirred atroom temperature for 20 minutes. The reaction mixture was diluted withdichloromethane, and the dilution was washed once with water, and oncewith brine. This is dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by chromatography over silica geleluting with toluene: ethyl acetate: acetic acid=250:250:1, to yield 107mg of compound 13 as colorless foam (84%), which contained 5% 1-α isomerresulting from this chromatography.

Compound 13: ¹ H-NMR (CDCl₃) δ:8.24 (2H, d, J=8.6 Hz), 7.54 (2H, d,J=8.6 Hz), 5.34 and 5.27 (2H, ABq, J=13.3 Hz), 4.75 (1H, s), 4.34 (1H,quintet, J=6.5 Hz), 4.25 (1H, dd, J=2.2 Hz, 7.8 Hz), 3.28 (1H, dd, J=2.2Hz, 6.5 Hz), 2.84 (1H, quintet, J=7.8 Hz), 1.39 (3H, d, J=6.5 Hz), 1.23(3H, d, J=7.8 Hz). IR (CHCl₃)cm⁻¹ : 3590, 3500 (br), 1760, 1605, 1523,1455, 1375, 1345.

What is claimed is:
 1. A compound of the formula: ##STR16## wherein R¹is hydrogen, alkyl which is optionally substituted by halogen or hydroxywhich may be substituted by a hydroxy-protecting group, or amino whichis optionally substituted by an amino-protecting group;R² is acarboxy-protecting group; R³ is aryl which is optionally substituted byhalogen, lower alkyl, lower alkoxy, hydroxy, amino, or nitro; X is--SCH₂ --, --OCH₂ --, --CH₂ CH₂ --, or C_(n) H_(2n+1) CH═(n=0-5), eachof which is optionally substituted by lower alkyl, lower alkoxy, loweralkylthio, aryl or lower alkenyl.
 2. A compound according to claim 1 inwhich R³ is phenyl.
 3. A compound according to claim 1 in which X is--SCH₂ --, --OCH₂ --, --CH₂ CH₂ -- or CH₃ CH═.